The present invention is directed to processes for the preparation of compounds of Formula (I):
where Ar and ALK are defined as below. Compounds of Formula (I) are modulators of serotonin receptors, and are useful in methods for treating or preventing diseases and conditions mediated by serotonin receptors, particularly the 5HT7 and/or 5HT2 receptor subtypes. Said compounds were disclosed in US Pat. Appl. Publ. US 20050119295, published Jun. 2, 2005, which is hereby incorporated by reference. More particularly, the compounds are useful for treating or preventing CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems. In addition, the compounds may be used in the treatment or prevention of a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.
Substituted pyrazoles are important synthetic targets in the pharmaceutical industry, as the pyrazole motif makes of the core structure of numerous biologically active compounds (Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets in Heterocyclic Systems 2002, 6, 52-98) including marketed drugs such as sildenafil (Terrett, N. K. et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) and celecoxib (Penning, T. D. et al. J. Med. Chem. 1997, 40, 1347-1365). Pyrazoles are often prepared by the reaction of hydrazines with 1,3-dicarbonyl compounds or their equivalents, such as α,β-ethynylketones or esters. These condensation reactions generally result in mixtures of regioisomers, which complicates isolation and purification processes. Cyclization reactions of 1,3-dipoles such as deazoalkanes or nitrilimines with olefins has also been used, but these reactions often suffer from low yields and harsh conditions (Elguero, J. Comp. Heterocycl. Chem. 1984, 5, 167; Elguero, J. Comp. Heterocycl. Chem. II 1996, 3, 1-75 and 817-932, and references cited therein). These processes are therefore unsuitable for large scale production of substituted pyrazoles.
Thus, there remains a need for a process for the preparation of fused pyrazole compounds, wherein a pyrazole regioisomer of Formula (I), as hereinafter defined, is preferentially prepared.
To this end, condensation of nitroalkenes with hydrazones was investigated. Nitroalkenes have been used in the formation of other heterocyclic systems (Meyer, H. Justus Liebigs Ann. Chem. 1981, 1534-1544; Gomez-Sanchez, A. et al. J. Chem. Res. (S) 1985, 318-319). However, the reaction between a hydrazone and a nitroalkene, neat or in Et2O, was shown to produce only nitro-pyrazolidine products, which further oxidized upon standing to give nitro-pyrazoles (Snider, B. B. et al. J. Org. Chem. 1979, 44(2), 218-221; Equation 1). Snider and co-workers noted that despite their investigation of a variety of conditions, they were unable to obtain any other products from the reaction.
In a subsequent report, reaction of a hydrazone with a nitroolefin in a DMF/H2O mixture did form a pyrazole without the nitro substituent (Gomez Guillen, M.; Jimenez, J. L. C. Carbohydrate Res. 1988, 180, 1-17; Equation 2).

The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety.